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- First Approval for TUKYSA Outside of the U.S. -
- Switzerland’s First Approval Under FDA Initiative Project Orbis -
Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that the Swiss Agency for Therapeutic Products (Swissmedic) has granted approval for TUKYSA™ (tucatinib) tablets in combination with trastuzumab and capecitabine, for the treatment of patients with metastatic HER2-positive breast cancer, who have previously received two or more anti-HER2 regimens in any setting, including trastuzumab, pertuzumab and trastuzumab-emtansine (T–DM1).
The application for TUKYSA approval was reviewed by Swissmedic as part of Project Orbis, an initiative of the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among participating international regulatory agencies in Canada, Australia and Singapore. On April 17, the FDA approved TUKYSA in the U.S. under the FDA’s Real-Time Oncology Review (RTOR) pilot program, four months prior to its action date, and represented the first new drug approved under Project Orbis.
"We’re grateful to Swissmedic for their collaboration through FDA’s Project Orbis in approving this important new medicine in Switzerland," said Jennifer Stephens, Vice President of Regulatory Affairs at Seattle Genetics. "We're committed to bringing new targeted therapies to patients, and we are excited about this important first step toward making TUKYSA available to patients in Switzerland."
TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth.i,ii
The approval is based on results from the pivotal trial HER2CLIMB, a randomized (2:1), double-blind, placebo-controlled trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). The study results were published in The New England Journal of Medicine in December 2019.
About HER2-Positive Breast Cancer
Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In 2018, more than two million new cases of breast cancer were diagnosed worldwide, including 522,513 in Europe. iii Between 15 and 20 percent of breast cancer cases are HER2-positive.iv Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.v,vi,vii Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.viii,ix,x
About TUKYSA (tucatinib)
TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.xi In the U.S., TUKYSA is approved in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
Important U.S. Safety Information
Warnings and Precautions
Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.
If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 5% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.
Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).
The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations
Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing Information for TUKYSA here.
About Seattle Genetics
Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people’s lives. ADCETRIS® (brentuximab vedotin) and PADCEVTM (enfortumab vedotin-ejfv) use the company’s industry-leading antibody-drug conjugate (ADC) technology. ADCETRIS is approved in certain CD30-expressing lymphomas, and PADCEV is approved in certain metastatic urothelial cancers. TUKYSATM (tucatinib), a small molecule tyrosine kinase inhibitor, is approved in certain HER2-positive metastatic breast cancers. The company is headquartered in Bothell, Washington, with locations in California, Switzerland and the European Union. For more information on our robust pipeline, visit www.seattlegenetics.com and follow @SeattleGenetics on Twitter.
Forward Looking Statements
Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of TUKYSA including its efficacy, safety and therapeutic uses including the potential use of TUKYSA in combination with trastuzumab and capecitabine for the treatment of patients with metastatic HER2-positive breast cancer, who have previously received two or more anti-HER2 regimens in any setting, including trastuzumab, pertuzumab and trastuzumab-emtansine (T–DM1) and the potential to bring TUKYSA to patients in Switzerland. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include reimbursement processes, the extent of reimbursement, the possibility that adverse events or safety signals may occur, the possibility that the ultimate utilization and adoption of TUKYSA by prescribing physicians may be limited, including due to impacts related to the COVID-19 pandemic, the possibility of difficulties in supplying and commercializing a new therapeutic agent, and the possibility of adverse regulatory actions. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption "Risk Factors" included in the company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
i TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.
ii Anita Kulukian, Patrice Lee, Janelle Taylor, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor ModelsMol Cancer Ther 2020;19:976-987.
iii Breast. Globocan 2018. World Health Organization. 2019. https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
iv Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785): 177-82.
v Loibli S, Gianni L. HER2-positive breast cancer. Lancet. 2017; 389(10087): 2415-29.
vi Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785): 177-82.
vii Breast Cancer HER2 Status. American Cancer Society website. www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed March 9, 2020.
viii Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37:1081-1089.
ix Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22:525-531.
x Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972-2977.
xi TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc.
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